Estrogen-containing patches have been known for some time. However, they have the disadvantages that they either contain ethanol, or that there is the potential risk that the active substance recrystallizes in the course of time, or that they do not release estradiol in an amount sufficient for therapy.
It is known from DE-OS 32 05 258 and EP 0 285 563 to administer estradiol and ethanol at the same time in a patch formulation. However, the production of said patch is very expensive and the wearing comfort after application is low due to the lack of flexibility.
EP 0 285 563 describes a transdermal therapeutic system for the combined application of estrogens and gestagens. The reservoir comprises an active substance formulation, optionally a membrane, as well as ethanol used as percutaneous absorption improving agent. The active substance release is mainly controlled by the membrane. In the patch described therein, the adhesive has the mere function of fastening the patch to the skin. The fact that it can contribute to the control of the active substance release is not its main function, what is more, this is merely a side effect--probably not desired at all. The patch described there is a so-called "pouch patch" since the active substance preparation is present in a pouch consisting of an impermeable backing layer and a membrane having an adhesive layer. As a consequence of its complicated structure, the production of this patch is very expensive, since the individual components have to be manufactured separately and then joined to form a patch in an additional process step.
EP 0 275 716 describes a two-layer transdermal therapeutic system for the simultaneous administration of one or several estrogens dissolved or microdispersed in the polymeric layer. In addition to the active agents, the adhesive layer comprises substances improving the transdermal absorption. Polymeric and adhesive layer may consist of polyacrylates, silicones, or polyisobutylenes.
EP 0 072 251 describes a flexible, moisture-absorbing medical bandage. The substrate attached to the flexible backing layer consists of a hydrophilic matrix based on hydrophilic, high-molecular polysaccharides and/or polyacrylic acid, polyacrylamide, ethylene-vinyl-acetate-copolymers, and other polymers, as well as of a liquid phase based on a solution or emulsion of carbohydrate, proteins, and polyhydric alcohols, as well as different active substances, amongst others hormones. An essential feature of this invention is the hygroscopic adhesive.
EP 0 328 806 describes a membrane-free, transdermal therapeutic system whose matrix consists of a polyacrylate adhesive, a solvent, a polyoxyethylene ester as penetration enhancer, and estrogens, the derivatives and combinations thereof.
WO 87/07 138 describes an estradiol patch based on a backing layer, an active substance-containing matrix, and a pressure sensitive adhesive covered with a removable protective layer. The production of the matrix and the adhesive is effected in technologically very expensive operations by homogenizing, degassing, coating, drying and separating. According to an embodiment, the backing layer must be coated with a pressure sensitive adhesive, involving another operational step. The individual parts are joined together in a separate step. For this reason, the manufacture of this patch is very expensive and complicated.
U.S. Pat. No. 4,624,665 describes systems containing the active substance in micro-encapsulated form in the reservoir. The reservoir is embedded between a backing layer and a membrane. The outer edge of the system is provided with a pressure sensitive adhesive. The structure and the production of this system is very complicated, since the active substance must be micro-encapsulated and homogeneously distributed in a liquid phase which is then embedded between backing layer and membrane in additional process steps. Additionally, the system must then be provided with an adhesive edge and covered with a protective layer.
Additionally, EP 0 186 019 describes active substance patches in which water-swellable polymers are added to a rubber-adhesive-resin mass and from which estradiol can be released. It turned out, however, that the estradiol release from these active substance patches is too low and does not meet the therapeutic requirements.
DE-OS 20 06 969 describes a patch or a pressure sensitive adhesive bandage having systemic action, in which contraceptive substances are incorporated into the adhesive component or adhesive film. The adhesive film may consist of an acrylate.
DE-OS 39 33 460 describes an estrogen-containing active substance patch based on homo and/or copolymers having at least one derivative of the acrylic acid or with methacrylic acid in combination with water-swellable substances.
EP 0 430 491 describes a transdermal therapeutic system comprising components intensifying the penetration of estradiol. These include unsaturated fatty acids, their alkyl esters and glycerol or alkanediols, such as propanediol. This formulation has the disadvantages that the unsaturated fatty acids are sensitive to oxidation and are thus subject to a chemical modification; additionally, propanediol evaporates in an uncontrolled manner during the drying process so that an active substance-containing patch which meets the required constant composition cannot be manufactured.
Also, the transdermal system described in EP 0 371 496 has the disadvantage that it comprises oleic acid as penetration enhancer, which is sensitive to oxidation and therefore does not allow the production of a stable system whose properties do not change during storage.
EP 0 569 338 describes a patch for the transdermal administration of estradiol by using penetration enhancers. These include saturated and unsaturated fatty acids and propylene glycol. The unsaturated fatty acids have the disadvantage that they are sensitive to oxidation, and that propylene glycol evaporates in an uncontrolled manner during the drying process. For this reason, an estradiol-containing patch having the required constant composition which does not change during storage cannot be manufactured.
Additionally, it turned out that pressure sensitive adhesive transdermal therapeutic matrix systems comprising the active substance in a partially or completely dissolved form do not release estradiol in the amount required for a therapy. There have been attempts of eliminating this drawback by enlarging the surface of the active substance patches. However, this results in the fact that the patches partially peel off during the application period. Thus, the all-over contact to the skin which is required for the therapy is no longer ensured, and the active substance amount penetrating through the skin varies inadmissibly. For this reason, a therapy with a constant active substance administration cannot be ensured.